Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis

Abstract

Rapidly progressive glomerulonephritis (RPGN) is a clinical a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern (“crescents”) with accumulation of T cells and macrophages, and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 days after the induction of experimental RPGN. This suggests that targeting the HB-EGF/EGFR pathway could also be beneficial for treatment of human RPGN.

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

“…10,11,18,19 Recent studies by us and others indicate that administration of EGFR tyrosine kinase inhibitors can slow progression of diabetic nephropathy in experimental animals 17,20 To study the potential role of EGFR expressed in diabetic podocytes, we developed a podocyte-specific EGFR knockout mouse (EGFR podKO ) by crossing EGFR flox/flox mice 21 with Podocin.Cre mice 22 ( Figure 1A). Effective cleavage of the EGFR floxed gene was verified by PCR analysis of isolated glomerular genomic DNA, with excision of exon 3 of the EGFR encoding gene ( Figure 1B).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Progression from initial glomerular injury to glomerulosclerosis is mediated directly by injured cells and via an intensive crosstalk between glomerular cells (90)(91)(92)(93)(94)(95)(96) or even between tubular and glomerular cells (97).…”

“…Pathways contributing to podocyte injury and glomerulosclerosis (100) amongst others include the epidermal growth factor receptor (EGFR) (90), mTOR (101)(102)(103), angiotensin II (104), miR-193a (105), KLF-4 (106), adiponectin (107), RAP1GAP (82), or Rho-A (108). Apart from necrosis, apoptosis or mitotic catastrophe, migration of podocytes onto Bowman's capsule, has been suggested as a novel mechanism of podocytes loss (109,110).…”

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

“…ERK phosphorylation, and thereby activation, is increased in glomeruli and podocytes in response to angiotensin II infusion (49 -52), salt-sensitive hypertension (53), puromycin aminoglycoside nephropathy (54 -58), passive Heymann nephritis (59,60), rapidly progressive glomerulonephritis (61)(62)(63)(64), and diabetic nephropathy (65)(66)(67). Phospho-ERK levels in mesangial cells have been correlated with glomerular damage in IgA nephropathy (68).…”

“…Phospho-ERK levels in mesangial cells have been correlated with glomerular damage in IgA nephropathy (68). In podocytes, ERK has been implicated in mediating actin reorganization, cell migration, and proliferation (61) and in acting as a both proapoptotic (56, 69 -71) and antiapoptotic/prosurvival (58,60,(72)(73)(74) signal.…”